Biology subjects

Lynch, J. W.

Publications and source records attributed to Lynch, J. W..

2 recordsLinked to original sources

bioRxiv2021

Signatures of adaptive evolution in platyrrhine primate genomes

The family Cebidae (capuchin and squirrel monkeys) form a remarkable platyrrhine clade exhibiting among the largest primate encephalisation quotients. Each cebid lineage is characterised by notable lineage-specific traits, with capuchins showing striking similarities to Hominidae including high sensorimotor intelligence with tool use, advanced cognitive abilities, and behavioural flexibility. Here, we take a comparative genomics approach, analysing five cebid branches including successive lineages, to infer a stepwise timeline for cebid adaptive evolution. We uncover candidate targets of selection across various periods of cebid evolution that may underlie the emergence of lineage-specific traits. Our analyses highlight shifting and sustained selective pressures on genes related to brain development, longevity, reproduction, and morphology, including evidence for cumulative and diversifying neurobiological adaptations over cebid evolutionary history. In addition to generating a new, high-quality reference genome assembly for robust capuchins, our results lend to a better understanding of the adaptive diversification of this distinctive primate clade.

genomics↗

bioRxiv2021

Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit

NMDAR-dependent Ca2+ influx underpins multiple forms of synaptic plasticity. In the adult forebrain, the majority of synaptic NMDAR currents are mediated by GluN2A-containing NMDARs. These receptors are rapidly inserted into synapses during LTP; however, the underlying molecular mechanisms remain poorly understood. Here we show that GluN2A is phosphorylated at Ser-1459 by CaMKII in response to glycine stimulation that mimics LTP in primary neurons. Phosphorylation of Ser-1459 promotes GluN2A interaction with the SNX27-retromer complex, therefore enhancing the endosomal recycling of NMDARs. Loss of SNX27 or CaMKII function blocks the glycine-induced increase in GluN2A-NMDARs on the neuronal membrane. Interestingly, mutations of Ser-1459, including the rare S1459G human epilepsy variant, prolong decay times of NMDAR-mediated synaptic currents in heterosynapses by increasing the active duration of channel openings. Taken together, these findings not only identify a critical role of Ser-1459 phosphorylation in regulating the function of NMDARs, but also explain how the S1459G epilepsy variant dysregulates NMDAR function.

neuroscience↗